Uptake of high-density lipoprotein by scavenger receptor class B type 1 is associated with prostate cancer proliferation and tumor progression in mice

Abstract

High-density lipoprotein (HDL) metabolism is facilitated in part by scavenger receptor class B, type 1 (SR-B1) that mediates HDL uptake into cells. Higher levels of HDL have been associated with protection in other diseases, however, its role in prostate cancer is not definitive. SR-B1 is up-regulated in prostate cancer tissue, suggesting a possible role of this receptor in tumor progression. Here, we report that knockout (KO) of SR-B1 in both human and mouse prostate cancer cell lines through CRISPR/Cas9-mediated genome editing reduces HDL uptake into the prostate cancer cells and reduces their proliferation in response to HDL. In vivo studies using syngeneic SR-B1 WT (SR-B1+/+) and SR-B1 KO (SR-B1−/−) prostate cancer cells in WT and apolipoprotein-AI KO (apoA1-KO) C57BL/6J mice revealed that WT hosts, containing higher levels of total and HDL-cholesterol, grew larger tumors than apoA1-KO hosts with lower levels of total and HDL-cholesterol. Furthermore, SR-B1−/− prostate cancer cells formed smaller tumors in WT hosts than SR-B1+/+ cells in the same host model. Increased tumor volume was overall associated with reduced survival. We conclude that knocking out SR-B1 in prostate cancer tumors reduces HDL-associated increases in prostate cancer cell proliferation and disease progression.

Molecular Characterization of Cancer Associated Fibroblasts in Prostate Cancer

“…To validate the results of our preceding microarray analysis, we performed a real time PCR analysis of three highly differentiated genes MAP3K1, SCARB1, and S100A10. We selected these genes because their known biological functions indicate that they play a role in prostate cancer pathogenesis and/or progression [ 25 , 26 , 27 ]. MAP3K1 encodes a MEK kinase involved in the regulation of cell proliferation, SCARB1 plays an important role in the regulation of cell homeostasis by maintaining the level of cholesterol available in fibroblasts for androgen synthesis, and S100A10 controls migration of cancer-associated macrophages [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ].…”

Macrophage-derived cholesterol contributes to therapeutic resistance in prostate cancer

“…Lipid transporters and scavenger receptors have emerged as potential targets in various types of solid malignancies (53,54). In the ID8 ovarian cancer model, genetic ablation of Abca1 / Abcg1 in myeloid cells decreased tumor growth, although whether this was through altered macrophage function or reduced cholesterol transfer to tumor cells is unclear (38).…”

Prostate Cancer—Focus on Cholesterol

“…HDL particles return excessive intracellular cholesterol to the liver or intestine where it is recycled, excreted or delivered to the steroidogenic organs and utilized for hormone synthesis [ 35 ]. The multiligand membrane receptor protein scavenger receptor class B member 1 (SR-B1) binds to the HDL particle and facilitates cholesterol efflux from the cell, but also can facilitate cholesterol influx [ 36 , 37 ]. De novo cholesterol synthesis occurs in the cytoplasm and includes about 30 subsequent reactions.…”